Valve for osmotic devices

ABSTRACT

An osmotic delivery system for controlled delivery of a beneficial agent includes an implant capsule having a beneficial agent reservoir, an osmotic agent which expands on contact with fluid imbibed through a permeable membrane retained by the implant capsule, a delivery port, and a valve for opening and closing the delivery port. When the osmotic agent expands, a pressure is exerted against a separating member positioned between the beneficial agent reservoir and the osmotic agent. The separating member moves within the capsule, thereby forcing the valve to move a distance such that the beneficial agent can exit the reservoir through the delivery port.

This application is a continuation of U.S. patent application Ser. No.09/748,099, filed on Dec. 21, 2000, now U.S. Pat. No. 6,508,808, whichclaims priority under 35 U.S.C. §§119 and/or 365 to U.S. ProvisionalPatent Application Serial No. 60/171,305, filed Dec. 21, 1999, both ofwhich are incorporated herein by reference in their entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to osmotic delivery devices for deliveringbeneficial agents, and more particularly, to osmotic delivery deviceshaving an osmotic engine and a valve to prevent expulsion of thebeneficial agents.

2. Description of the Related Art

Controlled delivery of beneficial agents, such as drugs, in the medicaland veterinary fields has been accomplished by a variety of methods. Onemethod for controlled prolonged delivery of beneficial agents involvesthe use of osmotic delivery systems. These systems can be implantedwithin a body of a human or animal to release beneficial agents in acontrolled manner over a preselected time or administration period. Ingeneral, osmotic delivery systems operate by imbibing liquid from theoutside environment and releasing corresponding amounts of thebeneficial agent.

A known osmotic delivery system, commonly referred to as an “osmoticpump,” generally includes some type of a capsule or enclosure having asemipermeable portion which selectively passes water into an interior ofthe capsule containing a water-attracting osmotic agent. In one knownosmotic delivery system the walls of the capsule are substantiallyimpermeable to items within and outside the capsule. A membrane plug isinserted into one end of the capsule and acts as the semipermeableportion allowing water to pass into the interior of the capsule. Thedifference in osmolarity between the water-attracting osmotic agent andthe environment surrounding the capsule causes water to pass through themembrane plug into the capsule which in turn causes the beneficial agentwithin the capsule to be delivered through a delivery orifice. Thewater-attracting osmotic agent may be the beneficial agent delivered tothe patient; however, in most cases a separate osmotic agent is usedspecifically for its ability to draw water into the capsule.

When a separate osmotic agent is used, the osmotic agent may beseparated from the beneficial agent within the capsule by a movabledividing member or piston. The structure of the capsule is such that thecapsule does not expand when the osmotic agent takes in water andexpands. As the osmotic agent expands, it causes the piston to move andthe beneficial agent to be discharged through the delivery orifice atthe same rate as the liquid, which is typically water, enters theosmotic agent by osmosis. Osmotic delivery systems may be designed todeliver a beneficial agent at a controlled constant rate, a varyingrate, or in a pulsatile manner.

In the known osmotic delivery systems, an osmotic tablet is generallyused as the osmotic agent and is placed inside the capsule adjacent thepiston. A membrane plug is placed in an opening in the capsule throughwhich the tablet and piston were inserted. Known membrane plugs aretypically cylindrical members which seal the interior of the capsulefrom the exterior environment, permitting only certain liquid moleculesfrom the environment of use to permeate through the membrane plug intothe interior of the capsule. The rate that the liquid permeates throughthe membrane plug controls the rate at which the osmotic agent expandsand drives the beneficial agent from the delivery system through thedelivery orifice. The rate of delivery of the beneficial agent from theosmotic delivery system may be controlled by varying the size of thebeneficial agent delivery orifice, the osmotic material, a size andshape of the membrane plug, or the permeability coefficient of themembrane plug.

It is desirable to seal the beneficial agent delivery orifice of thedelivery system to prevent incursion of materials into the deliverysystem before sufficient osmotic pressure exists to insure a flow of thebeneficial agent through the orifice. Protecting the beneficial agentfrom the external environment is particularly important when thebeneficial agent is a protein formulation or other agent which breaksdown when in contact with certain environmental compositions.

In order to prevent contamination or early release of the beneficialagent, some delivery systems are provided with a plug in the orificewhich is discharged upon movement of the piston by the fluid pressurewithin the system. Typically, such osmotic delivery systems usemechanical plugs, bio-eroding, or dissolving plugs.

With mechanical plugs, such plugs are chemically stable materialsdischarged from the delivery system on movement of a piston containedwithin the system. Premature release of the beneficial agent may occurwhen the delivery system is jarred, thereby loosening the mechanicalplug from the system. Further, mechanical plugs expelled from thedelivery device may not be acceptable with the patient when left in thepatient's body at the implant site.

Bio-eroding or dissolving plugs also present drug delivery problemssince such plugs allow the drug delivery orifice to open regardless ofwhether or not the osmotic agent can exert sufficient hydraulic pressureto insure flow of the beneficial agent.

Because of the above-identified problems associated with current osmoticdelivery systems, it is desirable to prevent contamination of thebeneficial agent and to prevent beneficial agent leakage by providing adelivery orifice valve which is not expelled into the patient's body.

SUMMARY OF THE INVENTION

The present invention relates to osmotic delivery systems having anosmotic engine and a valve to prevent contamination and/or expulsion ofthe beneficial agents.

In accordance with one aspect of the present invention, a deliverysystem for controlled delivery of a beneficial agent includes animplantable capsule having a delivery orifice, a separating memberdividing the capsule into a beneficial agent reservoir and a drivingreservoir, an osmotic engine in the driving reservoir, and a valvemember that can move from a closed position to an open position. In theclosed position, the valve member prevents the expulsion of beneficialagent from the beneficial agent reservoir through the delivery orifice.The implantable capsule can include an attachable cap having a vent. Inoperation, the osmotic engine imbibes fluid thereby causing the engineto swell. This swelling causes the osmotic engine to exert a pressure onthe separating member whereby such pressure moves the separating member,the beneficial agent reservoir, and the valve member a distance suchthat the valve member moves to an open position, allowing passage ofbeneficial agent through the delivery orifice at a desired deliveryrate.

In accordance with another aspect of the present invention, a method ofpreventing contamination from entering the osmotic delivery devicebefore activation includes the steps of providing a delivery devicecapsule enclosing a first chamber which contains a beneficial agent anda valve member. The first chamber has an opening communicating with theexternal environment. Before activation of the delivery device, thevalve member occludes the opening. This occlusion prevents thebeneficial agent from leaving the device, as well as prevents theincursion of contaminants into the device.

In accordance with an additional aspect of the present invention, amethod of controlling an initial release of a beneficial agent from anosmotic delivery device includes the steps of providing a deliverydevice capsule which encloses a first chamber containing the beneficialagent, a valve member, and a second chamber containing an osmotic agent.The first chamber has a beneficial agent delivery orifice communicatingwith the external environment. The valve member is initially in a closedposition and blocks beneficial agent from passing through the beneficialagent delivery orifice. Upon implantation, the osmotic agent imbibessurrounding fluid to form an osmotic solute which expands and exerts apressure on the first chamber. The osmotic imbibition of surroundingfluid builds pressure within the osmotic engine until sufficient forceis exerted to move the first chamber and valve member, the valve membermoving from the closed position to an open position. With the valve inthe opened position, beneficial agent contained in the first chamber canpass through the beneficial agent delivery orifice to the externalenvironment.

The present invention provides the advantage of a more controllablebeneficial agent delivery rate by preventing expulsion of beneficialagent from the drug reservoir by using a valve to occlude the drugdelivery orifice. The valve does not allow beneficial agent to passthrough the delivery orifice until sufficient hydraulic pressure existsto displace the beneficial agent from the drug reservoir. Moreover, thepresent invention retains the valve within delivery device, wherebyremoving the implant from the patient after delivering the medicationallows retrieval of both the valve and the implant device.

BRIEF DESCRIPTION OF THE FIGURES

The invention will now be described in greater detail with reference tothe preferred embodiments illustrated in the accompanying drawings, inwhich like elements bear like reference numerals, and wherein:

FIG. 1 is a side cross-sectional view of an osmotic delivery deviceaccording to the present invention;

FIG. 2 is a side cross-sectional view of the osmotic delivery device ofFIG. 1 delivering a beneficial agent through an orifice;

FIG. 3 is a side cross-sectional view of an osmotic delivery systemhaving an alternative embodiment of a cap with the cap in closedposition; and

FIG. 4 is a side cross-sectional view of an osmotic delivery systemhaving an alternative embodiment of a cap with the cap in openedposition.

DETAILED DESCRIPTION

The present invention relates to an osmotic delivery system forcontrolled delivery of a beneficial agent. FIGS. 1-4 illustrate twoexamples of osmotic delivery devices 10 according to the presentinvention.

The osmotic drug delivery device 10, as illustrated in FIG. 1, includesa movable valve 28, a first chamber 22 containing a beneficial agent, aseparating member 20, and a second chamber 24 containing an osmoticengine or agent, all of which are enclosed within an elongatedsubstantially cylindrical enclosure or capsule 12. The capsule 12 has afirst end 14 and an open end 16. The first end 14 of the capsule 12 hasone or more orifices or ports 18 for delivering a beneficial agentcontained within a first chamber 22 of the osmotic delivery device 10 toan external environment. In most configurations, one delivery port 18will suffice. However, two or more delivery ports 18 may be presentwithout departing from the present invention.

The valve 28 occludes the delivery orifice 18 when the valve is in aclosed position, preventing the beneficial agent in the first chamber 22from leaving the delivery device 10 as well as preventing the incursionof foreign materials into the device. The dimensions of the valve 28 interms of both diameter and length are selected such that the valve willnot exit the delivery device 10 through the delivery orifice 18.

The separating member 20 also separates the first chamber 22 containingthe beneficial agent from the second chamber 24 containing the osmoticagent. The separating member 20 and valve 28 are substantiallycylindrical members which are configured to fit within the capsule 12and are slidably movable along a longitudinal direction within thecapsule. The separating member and valve 20, 28 preferably are formed ofa resilient material which is impermeable to the compositions within thecapsule 12, and at least a portion of the separating member 20 and thevalve 28 forms a seal with the inner surface of said capsule 12.

In addition, the movable separating member and valve 20, 28 may beflexible members such as pistons, partitions, pads, flat sheets,spheroids, or rigid metal alloys, and may be made of any number of inertmaterials. Furthermore, the osmotic device 10 may function without thepiston 20, having simply an interface between the osmotic agent and thebeneficial agent.

A semipermeable membrane 30 couples with the capsule 12 at the open end16 and encloses the second chamber 24 containing the osmotic agent. Theosmotic agent may be, for example, a nonvolatile water soluble osmagent,an osmopolymer which swells on contact with water, or a mixture of thetwo. The elongated capsule 12 is formed of a material which issufficiently rigid to withstand expansion of the osmotic agent containedwithin a second chamber 24 of the delivery device 10 without changingsize or shape. The elongated capsule 12 is preferably substantiallyimpermeable to fluids in the environment as well as to ingredientscontained within the osmotic delivery device 10 such that the migrationof such materials into or out of the device through the impermeablematerial of the capsule is so low as to have substantially no adverseimpact on the function of the osmotic delivery device.

As shown in FIGS. 1 and 2, the osmotic delivery device 10 of oneembodiment of the present invention includes a semipermeable membrane30, which is coupled with the open end 16 of the capsule 12. Inoperation, after placing the osmotic agent within the second chamber 24of the capsule, the semipermeable membrane 30 allows liquid to pass froman environment of use into the capsule 12 to cause the osmotic agent toswell. However, the material forming the semipermeable membrane 30 islargely impermeable to the materials within the capsule 12 and to otheringredients within the environment of use.

The swelling osmotic agent exerts a pressure on the separating member orpiston 20 and forces said separating member to move a distance D in adirection of the arrow A. The separating member 20 applies a force tothe beneficial agent in the first chamber 22, the beneficial agenttransfers the force to the valve 28. Accordingly, this force causes thevalve 28 to move a distance C from the close position to an openposition. A clearance 34 between the valve 28 and the first end 14decreases by the distance C. In the open position, the valve 28 allowsthe beneficial agent to pass through the delivery orifice 18 to theexternal environment of use.

The osmotic agent in conjunction with the separating member 20 drive thebeneficial agent from the first chamber 22 and insures a flow ofbeneficial agent out of the delivery orifice 18. The valve 28 isretained within the delivery device 10 at the closed first end 14 of thecapsule 12 and, as described above, the valve 28 has dimensions suchthat it will not leave the delivery device 10 through the deliveryorifice 18. In a preferred embodiment, the capsule 12 has a vent 32 atthe first end 14, allowing fluid to escape from the clearance 34 betweenthe valve 28 and the capsule 12 when the valve 28 moves toward the firstend 14.

Depending on the application, the clearance 34 between the valve 28 andthe capsule 12 may be filled with a bio-compatible liquid or gas. Theconfiguration of the osmotic delivery system and the material of thesemipermeable membrane 30 control the delivery rate of a beneficialagent from the osmotic delivery system.

In assembling the osmotic delivery device 10 according to the embodimentof the present invention shown in FIGS. 1 and 2, the capsule 12 isprepared by forming at least one vent 32 at the first end 14 of thecapsule. The vent 32 may be formed by mechanical drilling, laserdrilling, molding, or any other known method. The delivery port 18 is anorifice formed by conventional techniques which are known in the art.Included among these methods are mechanical drilling, laser drilling,and molding. The dimensions of the delivery port 18 in terms of bothdiameter and length will vary with the type of beneficial agent, therate at which the beneficial agent is to be delivered, and theenvironment into which it is to be delivered. The considerationsinvolved in determining the optimum dimensions of the delivery port 18for any particular capsule 12 or beneficial agent and the selection ofthe appropriate dimensions will be readily apparent to those skilled inthe art.

Once the capsule 12 of FIGS. 1 and 2 has been prepared with the vent 32and at least one delivery port 18, having a number, shape, and size toachieve a desired delivery rate of the beneficial agent, the valve 28 isinserted into the capsule 12 through the open end 16.

According to one embodiment of the present invention, the beneficialagent contained in the first chamber 22 of the capsule 12 is a flowablecomposition such as a liquid, suspension, or slurry, and is typicallypoured into the first chamber 22 of the capsule after the valve 28 hasbeen inserted. The separating member 20 is inserted into the capsule 12through the open end 16 and is positioned adjacent the beneficial agent.

Once the osmotic agent pellet(s) or tablet(s) have been formed, they areplaced inside the pre-formed capsule in the second chamber 24 adjacentthe separating member 20. Then the semipermeable membrane 30, accordingto one embodiment of the present invention, is placed into or over theopen end 16 of the capsule 12 to close off and seal the open end of theosmotic delivery system.

An alternative embodiment of the invention illustrated in FIGS. 3-4includes a cap 36 having a hollow interior and a substantially constantthickness cylindrical side wall 42 and an end wall 44. The cap 36 formsthe first end 50 of the capsule 12. In a preferred embodiment, the cap36 affixes to the body of the capsule 12 by a snap fitting mechanism 38,such as a barbed stake. The cap 36 preferably has a vent 48 in the endwall 44 which after assembly allows the valve 28 to move in a directiontowards the end wall 14. In a different embodiment, the cap 36 can bepivotally rotated about a hinge in a direction of the arrow B, asdepicted in FIG. 4.

The first chamber 22 of the osmotic delivery device 40 has at least oneopening 46 which communicates with the environment of use. As shown inFIG. 3, the opening 46 is formed in the body of the capsule 12 and ispositioned adjacent the contacting surfaces of the cap. Alternatively,the opening 46 can be formed in the cap 36 and positioned adjacent thecontacting surfaces of the body of the capsule 12. The semipermeablemembrane 30 couples with the capsule 12 at the opened second end 52.

In assembling the osmotic delivery device 10 according to the embodimentof the present invention shown in FIGS. 3 and 4, the cap 36 is preparedby forming at least one vent 48 at the end wall 44. The vent 48 may beformed by mechanical drilling, laser drilling, molding, or any otherknown method.

The capsule 12 is prepared having an opened first end 50 and an openedsecond end 52. The delivery port 46 is an orifice positioned at the edgeof the cap 36 adjacent the capsule 12, or the delivery port 46 ispositioned at the edge of the capsule 12 adjacent the cap 36. Thedelivery port 18 is formed by conventional techniques which are known inthe art. Included among these methods are laser drilling, mechanicaldrilling, grooving the edge of the capsule or cap, and molding.

The separating member 20 is inserted into the capsule 12 through thefirst or second end 50, 52. Once the osmotic agent pellet(s) ortablet(s) have been formed, they are placed inside the capsule 12 in thesecond chamber 24, adjacent the separating member 20. The semipermeablemembrane 30 is placed into or over the second end 52 to Lose off andseal that end.

Beneficial agent is added into the first chamber 22 of the capsule 12through the first end 50, and the valve 28 is inserted adjacent thebeneficial agent in a closed position. As discussed, the valve 28 in aclosed position prevents the beneficial agent from leaving the deliverydevice 10 and prevents incursion of foreign materials into the device.Then the cap 36 is placed at the first end 50 of the capsule to closeoff and seal that open end of the osmotic delivery system 10. The cap 36may be secured to the capsule 12 by press fitting, snap fitting,threading, adhesive, welding, staking, or the like.

In general, materials suitable for use in the movable separating member20 and the valve 28 are elastomeric materials including non-reactivepolymers, as well as elastomers in general, such as polyurethanes andpolyamides, chlorinated rubbers, styrene-butadiene rubbers, andchloroprene rubbers. The polymers include acrylonitrile polymers such asacrylonitrile-butadiene-styrene terpolymer, and the like, halogenatedpolymers such as polytetraflouroethylene, polychlorotrifluoroethylene,copolymer tetrafluoroethylene and hexafluoropropylene; polyimide;polysulfone; polycarbonate; polyethylene; polypropylene;polyvinylchloride-acrylic copolymer;polycarbonate-acrylonitrile-butadiene-styrene; polystyrene; and thelike.

Semipermeable compositions suitable for the semipermeable membrane 30are well known in the art, examples of which are disclosed in U.S. Pat.No. 4,874,388, the entire disclosure of which is incorporated herein byreference. Such possible semipermeable materials from which the membrane30 can be made include, but are not limited to, for example, Hytrelpolyester elastomers (DuPont), cellulose esters, cellulose ethers, andcellulose ester-ethers, water flux enhanced ethylene-vinyl acetatecopolymers, semipermeable membranes made by blending a rigid polymerwith water-soluble low molecular weight compounds, and othersemipermeable materials well known in the art. The above cellulosicpolymers have a degree of substitution, D.S., on the anhydroglucoseunit, from greater than 0 up to 3 inclusive. By “degree of substitution”or “D.S.” is meant the average number of hydroxyl groups originallypresent on the anhydroglucose unit comprising the cellulose polymer thatare replaced by a substituting group. Representative materials include,but are not limited to, one selected from the group consisting ofcellulose acylate, cellulose diacylate, cellulose triacylate, celluloseacetate, cellulose diacetate, cellulose triacetate, mono-, di-, andtricellulose alkanylates, mono-, di-, and tricellulose aroylates, andthe like. Exemplary cellulosic polymers include cellulose acetate havinga D.S. up to 1 and an acetyl content up to 21%; cellulose acetate havinga D.S. of 1 to 2 and an acetyl content of 21% to 35%; cellulose acetatehaving a D.S. of 2 to 3 and an acetyl content of 35% to 44.8%, and thelike. More specific cellulosic polymers include cellulose propionatehaving a D.S. of 1.8 and a propionyl content of 39.2% to 45% and ahydroxyl content of 2.8% to 5.4%; cellulose acetate butyrate having aD.S. of 1.8 and an acetyl content of 13% to 15% and a butyryl content of34% to 39%; cellulose acetate butyrate having an acetyl content of 2% to29%, a butyryl content of 17% to 53%, and a hydroxyl content of 0.5% to4.7%; cellulose acetate butyrate having a D.S. of 1.8, an acetyl contentof 4% average weight percent, and a butyryl content of 51%; cellulosetriacylates having a D.S. of 2.9 to 3 such as cellulose trivalerate,cellulose trilaurate, cellulose tripalmitate, cellulose trisuccinate,and cellulose trioctanoate; cellulose diacylates having a D.S. of 2.2 to2.6 such as cellulose disuccinate, cellulose dipalmitate, cellulosedioctanoate, cellulose dipentate; coesters of cellulose such ascellulose acetate butyrate and cellulose, cellulose acetate propionate,and the like.

Other materials for the membrane 30 are polyurethane,polyetherblockamide (PEBAX, commercially available from ELF ATOCHEM,Inc.), and injection-moldable thermoplastic polymers with somehydrophilicity such as ethylene vinyl alcohol (EVA). In general, themembrane 30 is made from semipermeable materials having a water uptakeranging from 1% to 80% but preferably less than 50%. The composition ofthe semipermeable membrane 30 is permeable to the passage of externalliquids such as water and biological liquids, and it is substantiallyimpermeable to the passage of beneficial agents, osmopolymers,osmagents, and the like.

Materials which may be used for the capsule 12 and the cap 36 must besufficiently strong to ensure that the capsule will not leak, crack,break, or distort under stresses to which it is subjected duringimplantation or under stresses due to the pressures generated duringoperation. The capsule 12 may be formed of chemically inert andbiocompatible, natural or synthetic materials which are known in theart. The capsule material is preferably a nonbioerodible material whichremains in the patient after use, such as titanium or a titanium alloy,and is largely impermeable to materials within and outside the capsule.However, the material of the capsule 12 may alternatively be abioerodible material which bioerodes in the environment after dispensingof the beneficial agent. Generally, preferred materials for the capsule12 are those acceptable for animal and human implants.

In general, typical materials of construction suitable for the capsule12 according to the present invention include non-reactive polymers orbiocompatible metals or alloys. Metallic materials useful for thecapsule 12 include stainless steel, titanium, platinum, tantalum, gold,and their alloys, as well as gold-plated ferrous alloys, platinum-platedferrous alloys, cobalt-chromium alloys and titanium nitride coatedstainless steel.

The capsule 12 may be formed from any of the wall-forming materialsdisclosed above by the use of a mold, with the materials applied eitherover the mold or inside the mold, depending on the mold configuration.Any of the wide variety of techniques known in the pharmaceuticalindustry may be used to form the capsule 12.

The osmotic agent is a liquid-attracting agent used to drive the flow ofthe beneficial agent. The osmotic agent may be an osmagent, anosmopolymer, or a mixture of the two. Species which fall within thecategory of osmagent, i.e., the non-volatile species which are solublein water and create the osmotic gradient driving the osmotic inflow ofwater, vary widely. Examples are well known in the art and includemagnesium sulfate, magnesium chloride, potassium sulfate, sodiumchloride, sodium sulfate, lithium sulfate, sodium phosphate, potassiumphosphate, d-mannitol, sorbitol, inositol, urea, magnesium succinate,tartaric acid, raffinose, and various monosaccharides, oligosaccharidesand polysaccharides such as sucrose, glucose, lactose, fructose, anddextran, as well as mixtures of any of these various species.

Species which fall within the category of osmopolymer are hydrophilicpolymers that swell upon contact with water, and these vary widely aswell. Osmopolymers may be of plant or animal origin, or synthetic, andexamples of osmopolymers are well known in the art. Examples include:poly(hydroxyalkyl methacrylates) with molecular weight of 30,000 to5,000,000, poly(vinylpyrrolidone) with molecular weight of 10,000 to360,000, anionic and cationic hydrogels, polyelectrolyte complexes,poly(vinyl alcohol) having low acetate residual, optionally cross linkedwith glyoxal, formaldehyde, or glutaraldehyde and having a degree ofpolymerization of 200 to 30,000, a mixture of methyl cellulose, crosslinked agar and carboxymethylcellulose, a mixture of hydroxyproplmethycellulose and sodium carboxymethylcellulose, polymers ofN-vinyllactams, polyoxyethylene-polyoxypropylene gels,polyoxybutylene-polyethylene block copolymer gels, carob gum,polyacrylic gels, polyester gels, polyuria gels, polyether gels,polyamide gels, polypeptide gels, polyamino acid gels, polycellulosicgels, carbopol acidic carboxy polymers having molecular weights of250,000 to 4,000,000, Cyanamer polyacrylamides, cross linkedindene-maleic anhydride polymers, Good-Rite polyacrylic acids havingmolecular weights of 80,000 to 200,000, Polyox Polyethylene oxidepolymers having molecular weights of 100,000 to 5,000,000, starch graftcopolymers, and Aqua-Keeps acrylate polymer polysaccharides.

The osmotic agent may be a solid osmotic tablet or a fluid osmoticagent. The osmotic tablet may be formed in many different conceivableshapes, textures, densities, and consistencies and still be within theconfines of the present invention. The osmotic agent may be manufacturedby a variety of techniques, many of which are known in the art. In onesuch technique, the osmotically active agent is prepared as solid orsemi-solid formulation and pressed into pellets or tablets whosedimensions correspond to slightly less than the internal dimensions ofthe respective chambers which they will occupy in the capsule interior.Depending on the nature of the materials used, the agent and other solidingredients which may be included may be processed prior to theformation of the pellets by such procedures as ballmilling, calendaring,stirring, or rollmilling to achieve a fine particle size and hencefairly uniform mixtures of each.

The present invention applies to the administration of beneficial agentsin general, which include any physiologically or pharmacologicallyactive substance. Drug agents which may be delivered by the presentinvention include drugs which act on the peripheral nerves, adrenergicreceptors, cholinergic receptors, the skeletal muscles, thecardiovascular system, smooth muscles, the blood circulatory system,synoptic sites, neuroeffector junctional sites, endocrine and hormonesystems, the immunological system, the reproductive system, the skeletalsystem, autacoid systems, the alimentary and excretory systems, thehistamine system and the central nervous system. Suitable agents may beselected from, for example, proteins, enzymes, hormones,polynucleotides, nucleoproteins, polysaccharides, glycoproteins,lipoproteins, polypeptides, steroids, analgesics, local anesthetics,antibiotic agents, anti-inflammatory corticosteroids, ocular drugs andsynthetic analogs of these species.

Examples of drugs which may be delivered by devices according to thisinvention include, but are not limited to prochlorperzine edisylate,ferrous sulfate, aminocaproic acid, mecamylamine hydrochloride,procainamide hydrochloride, amphetamine sulfate, methamphetaminehydrochloride, benzamphetamine hydrochloride, isoproterenol sulfate,phenmetrazine hydrochloride, bethanechol chloride, methacholinechloride, pilocarpine hydrochloride, atropine sulfate, scopolaminebromide, isopropamide iodide, tridihexethyl chloride, phenforminhydrochloride, methylphenidate hydrochloride, theophylline cholinate,cephalexin hydrochloride, diphenidol, meclizine hydrochloride,prochlorperazine maleate, phenoxybenzamine, thiethylperzine maleate,anisindone, diphenadione erythrityl tetranitrate, digoxin,isoflurophate, acetazolamide, methazolamide, bendroflumethiazide,chloropromaide, tolazamide, chlormadinone acetate, phenaglycodol,allopurinol, aluminum aspirin, methotrexate, acetyl sulfisoxazole,erythromycin, hydrocortisone, hydrocorticosterone acetate, cortisoneacetate, dexamethasone and its derivatives such as betamethasone,triamcinolone, methyltestosterone, 17-S-estradiol, ethinyl estradiol,ethinyl estradiol 3-methyl ether, prednisolone, 17-∝hydroxyprogesteroneacetate, 19-nor-progesterone, norgestrel, norethindrone, norethisterone,norethiederone, progesterone, norgesterone, norethynodrel, aspirin,indomethacin, naproxen, fenoprofen, sulindac, indoprofen, nitroglycerin,isosorbide dinitrate, propranolol, timolol, atenolol, alprenolol,cimetidine, clonidine, imipramine, levodopa, chlorpromazine, methyldopa,dihydroxyphenylalanine, theophylline, calcium gluconate, ketoprofen,ibuprofen, cephalexin, erythromycin, haloperidol, zomepirac, ferrouslactate, vincamine, diazepam, phenoxybenzamine, diltiazem, milrinone,capropril, mando, quanbenz, hydrochlorothiazide, ranitidine,flurbiprofen, fenufen, fluprofen, tolmetin, alclofenac, mefenamic,flufenamic, difuinal, nimodipine, nitrendipine, nisoldipine,nicardipine, felodipine, lidoflazine, tiapamil, gallopamil, amlodipine,mioflazine, lisinolpril, enalapril, enalaprilat, captopril, ramipril,famotidine, nizatidine, sucralfate, etintidine, tetratolol, minoxidil,chlordiazepoxide, diazepam, amitriptyline, and imipramine. Furtherexamples are proteins and peptides which include, but are not limitedto, insulin, colchicine, glucagon, thyroid stimulating hormone,parathyroid and pituitary hormones, calcitonin, renin, prolactin,corticotrophin, thyrotropic hormone, follicle stimulating hormone,chorionic gonadotropin, gonadotropin releasing hormone, bovinesomatotropin, porcine somatotropin, oxytocin, vasopressin, GRF,prolactin, somatostatin, lypressin, pancreozymin, luteinizing hormone,LHRH, LHRH agonists and antagonists, leuprolide, interferons,interleukins, growth hormones such as human growth hormone, bovinegrowth hormone and porcine growth hormone, fertility inhibitors such asthe prostaglandins, fertility promoters, growth factors, coagultionfactors, human pancreas hormone releasing factor, analogs andderivatives of these compounds, and pharmaceutically acceptable salts ofthese compounds, or their analogs or derivatives.

On the molecular level, the various forms of the beneficial agent mayinclude uncharged molecules, molecular complexes, and pharmaceuticallyacceptable acid addition and base addition salts such as hydrochlorides,hydrobromides, acetate, sulfate, laurylate, oleate, and salicylate. Foracidic compounds, salts of metals, amines or organic cations may beused. Derivatives such as esters, ethers and amides can also be used. Abeneficial agent can be used alone or mixed with other agents. Thebeneficial agent may optionally include pharmaceutically acceptablecarriers and/or additional ingredients such as antioxidants, stabilizingagents, permeation enhances, and the like.

Animals to whom beneficial agents may be administered using systems ofthis invention include humans and other animals. The invention is ofparticular interest for application to humans and household, sport, andfarm animals, particularly mammals. For the administration of beneficialagents to animals, the devices of the present invention may be implantedsubcutaneously or intraperitoneally wherein aqueous body fluids areavailable to activate the osmotic agent. Devices of the invention mayalso be administered to the rumen of ruminant animals, in whichembodiment the devices may further comprise a density element formaintaining the device in the rumen for extended periods of time of upto 120 days or longer. Density elements are well known in the art ofdrug delivery devices.

The delivery devices of this invention are also useful in environmentsoutside of physiological or aqueous environments. For example, thedelivery devices may be used in intravenous systems (attached to an IVpump or bag or to an IV bottle, for example) for delivering beneficialagents to an animal, primarily to humans. They may also be utilized inblood oxygenators, kidney dialysis and electrophoresis, for example.Additionally, delivery devices of the present invention may be used inthe biotechnology area, such as to deliver nutrients or growthregulating compounds to cell cultures. In such instances, activatingmechanisms such as mechanical mechanisms are particularly useful. Thebeneficial agent may be any of the agents which are known to bedelivered to the body of a human or an animal such as medicaments,vitamins, nutrients, or the like. The beneficial agent may also be anagent which is delivered to other types of aqueous environments such aspools, tanks, reservoirs, and the like. Included among the types ofagents which meet this description are biocides, sterilization agents,nutrients, vitamins, food supplements, sex sterilants, fertilityinhibitors and fertility promoters.

While the invention has been described in detail with reference topreferred embodiments thereof, it will be apparent to one skilled in theart that various changes can be made, and equivalents employed withoutdeparting from the invention.

What is claimed is:
 1. An osmotic delivery device for delivery of abeneficial agent, comprising: an implantable capsule having a beneficialagent delivery orifice, the beneficial agent delivery orifice positionedbetween a first end and a second end of the implantable capsule; aseparating member positioned within the capsule between the first andsecond ends, the separating member dividing said capsule into abeneficial agent reservoir and a driving reservoir; an osmotic agentpositioned in the driving reservoir; and a valve member positioned withan interior of the capsule between the first end and the beneficialagent reservoir such that the valve member opens and closes thebeneficial agent delivery orifice.
 2. The osmotic delivery device ofclaim 1, wherein the valve member is positioned within the capsule suchthat it separates the beneficial agent reservoir from a separateclearance area within the capsule.
 3. The osmotic delivery device ofclaim 1, wherein the implantable capsule has an inner surface and anouter surface, and the valve member is positioned adjacent to the innersurface.
 4. The osmotic delivery device of claim 1, further comprising apermeable membrane retained by the capsule and separating the osmoticagent from a surrounding fluid, wherein in operation, the osmotic agentimbibes the surrounding fluid through the permeable membrane, saidosmotic agent forming an osmotic solute which exerts a pressure on theseparating member and forces said separating member to move within thecapsule, thereby moving the valve member to allow delivery of thebeneficial agent through the beneficial agent delivery orifice.
 5. Theosmotic delivery device of claim 4, wherein the permeable membraneretained by the capsule controls a rate at which the surrounding fluidis imbibed into the osmotic agent, the rate at which said surroundingfluid is imbibed into the osmotic agent controlling a delivery rate ofthe beneficial agent.
 6. The osmotic delivery device of claim 1, whereinthe first end of the capsule includes a vent which allows fluid trappedbetween the valve member and the first end to escape from the capsule asthe valve member moves.
 7. The osmotic delivery device of claim 1,wherein the capsule provides a clearance between the valve member andthe first end, wherein the clearance can receive at least a portion ofsaid valve member in an open position.
 8. The osmotic delivery device ofclaim 1, wherein at least a portion of the separating member forms aseal with an inner surface of the capsule.
 9. The osmotic deliverydevice of claim 1, wherein at least a portion of the valve member has alength greater than a diameter of the beneficial agent delivery orifice.10. The osmotic delivery device of claim 1, further comprising a capforming the first end of the capsule, the cap capable of receiving atleast a portion of said valve member.
 11. The osmotic delivery device ofclaim 10, wherein the cap is attachable to a body of the capsule with asnap fitting mechanism.
 12. The osmotic delivery device of claim 10,wherein the cap is hingedly attached to a body of the capsule.
 13. Theosmotic delivery device of claim 1, wherein the separating member ismovable within the capsule.
 14. An osmotic delivery device, comprising:an implantable capsule having first and second ends, the capsulecontaining an osmotic agent and a beneficial agent; and a beneficialagent delivery orifice located adjacent to a valve member, wherein thevalve member is positioned within an interior of the capsule and movablefrom a closed position to an open position in response to fluid pressurecreated by the osmotic agent, in the closed position the valve memberblocks fluid flow through the beneficial agent delivery orifice, and inthe open position allows passage of fluid through the beneficial agentdelivery orifice.
 15. The osmotic delivery device of claim 14, furthercomprising a cap forming the first end of the capsule.
 16. The osmoticdelivery device of claim 15, wherein the beneficial agent deliveryorifice is positioned adjacent the cap.
 17. The osmotic delivery deviceof claim 14, further comprising: a movable separating member between theosmotic agent and the beneficial agent; and a permeable membraneretained by the capsule and separating the osmotic agent from asurrounding fluid, wherein in operation, the osmotic agent imbibes thesurrounding fluid through the permeable membrane, said osmotic agentforming an osmotic solute which exerts a pressure on the separatingmember and forces said separating member to move within the capsule,thereby moving the valve member to allow delivery of the beneficialagent through the beneficial agent delivery orifice.
 18. A method ofpreventing contamination from entering an osmotic delivery device beforeactivation, comprising the steps of: providing a delivery device capsulewhich encloses a first chamber containing a beneficial agent, the firstchamber having a beneficial agent delivery orifice communicating with anexternal environment, and a valve member movable within the capsule; andpositioning the valve member in the delivery device capsule, such thatthe valve member occludes the beneficial agent delivery orifice.
 19. Themethod of claim 18, further comprising the step of providing an osmoticagent which imbibes a surrounding fluid into the osmotic agent to forman osmotic solute which expands and exerts a pressure on the beneficialagent and the valve member, wherein the pressure moves the valve memberto a position wherein the valve member does not occlude the beneficialagent delivery orifice.
 20. The method of claim 19, further comprisingthe step of providing a movable separating member between the osmoticagent and the beneficial agent such that the valve member in the openedposition allows the separating member to drive the beneficial agent fromthe first chamber, thereby insuring a flow of beneficial agent throughthe beneficial agent delivery orifice and preventing contamination fromentering the delivery device.
 21. A method of controlling an initialrelease of a beneficial agent from an osmotic delivery device,comprising the steps of: providing a delivery device capsule whichencloses a first chamber containing a beneficial agent, a valve member,and a second chamber containing an osmotic agent, wherein the firstchamber has a beneficial agent delivery orifice; positioning the valvemember in the delivery device capsule, wherein before activation thevalve member occludes the delivery orifice preventing passage of thebeneficial agent contained in the first chamber through the beneficialagent delivery orifice; and imbibing a surrounding fluid into theosmotic agent to form an osmotic solute which expands and exerts apressure on the beneficial agent and the valve member, wherein thepressure moves the valve member to a position allowing the beneficialagent contained in the first chamber to pass through the beneficialagent delivery orifice.
 22. An osmotic delivery device for delivery of abeneficial agent, comprising: an implantable capsule having a hollowinterior and substantially cylindrical side wall and a first end walland a second end wall, the implantable capsule including: a cap formingthe first end wall of the implantable capsule; and a capsule bodyforming the second end wall of the capsule; a beneficial agent deliveryorifice positioned in the cylindrical sidewall between the first andsecond ends; a separating member positioned within the capsule betweenthe first and second ends, the separating member dividing said capsuleinto a beneficial agent reservoir and a driving reservoir; an osmoticagent positioned in the driving reservoir; and a valve member positionedwithin the capsule between the first end and the beneficial agentreservoir such that the valve member occludes the beneficial agentdelivery orifice in a first position and allows delivery of a beneficialagent in a second position.
 23. The osmotic delivery device of claim 22,wherein the cap affixes to the body of the capsule by a snap fittingmechanism.
 24. The osmotic delivery device of claim 23, wherein the snapfitting mechanism is a barbed stake.
 25. The osmotic delivery device ofclaim 22, wherein the cap has a vent in the end wall which afterassembly allows the valve to move in a direction towards the end wall.26. The osmotic delivery device of claim 22, wherein the cap affixes tothe capsule body by a hinge.
 27. The osmotic delivery device of claim22, wherein the capsule has at least one opening which communicates withthe environment of use.
 28. The osmotic delivery device of claim 27,wherein the opening is formed in the capsule body and is positionedadjacent a capsule contacting surface of the cap.
 29. The osmoticdelivery device of claim 27, wherein the opening is formed in the capand positioned adjacent a cap contacting surface of the capsule body.30. The osmotic delivery device of claim 22, wherein the semi-permeablemembrane couples with the capsule at the opened second end.
 31. Theosmotic delivery device of claim 22, wherein the delivery orifice ispositioned at an edge of the cap adjacent the capsule.
 32. The osmoticdelivery device of claim 22, wherein the delivery orifice is positionedat an edge of the capsule adjacent the cap.
 33. The osmotic deliverydevice of claim 22, wherein said valve member is movable in alongitudinal direction within said capsule.
 34. The osmotic deliverydevice of claim 22, further comprising a permeable membrane retained bythe capsule and separating the osmotic agent from a surrounding fluid,wherein in operation, the osmotic agent imbibes the surrounding fluidthrough the permeable membrane, said osmotic agent forming an osmoticsolute which exerts a pressure on the separating member and forces saidseparating member to move within the capsule, thereby moving the valvemember to allow delivery of the beneficial agent through the beneficialagent delivery orifice.
 35. The osmotic delivery device of claim 34,wherein the permeable membrane retained by the capsule controls a rateat which the surrounding fluid is imbibed into the osmotic agent, therate at which said surrounding fluid is imbibed into the osmotic agentcontrolling a delivery rate of the beneficial agent.
 36. The osmoticdelivery device of claim 22, wherein a vent allows fluid trapped betweenthe valve member and the cap to escape from the capsule as the valvemember moves.
 37. The osmotic delivery device of claim 22, wherein thecapsule provides a clearance between the valve member and the first end,wherein the clearance can receive at least a portion of said valvemember in an open position.
 38. The osmotic delivery device of claim 22,wherein at least a portion of the separating member forms a seal with aninner surface of the capsule.
 39. The osmotic delivery device of claim22, wherein at least a portion of the valve member has a length greaterthan a diameter of the beneficial agent delivery orifice.